MTHFD2 is one of the isoforms of MTHFD, which is an enzyme involved in folate metabolism, and present in mitochondria. MTHFD2 is a bifunctional enzyme catalyzing a NAD+ dependent methylene-tetrahydrofolate dehydrogenase reaction and a methenyltetrahydrofolate cyclohydrolase reaction. The NAD+ dependent methylene-tetrahydrofolate dehydrogenase reaction is a reaction using 5,10-methylenetetrahydrofolate as a substrate to produce 5,10-methenyltetrahydrofolate. The methenyltetrahydrofolate cyclohydrolase reaction is a reaction using 5,10-methenyltetrahydrofolate as a substrate to produce 10-formyltetrahydrofolate.
Recently, it was reported that MTHFD2 can serve as a potential target molecule for cancer treatment (Non Patent Literature 1). More specifically, it was reported that MTHFD2 expression is remarkably enhanced in various cancers both at a mRNA level and at a protein level; and that enhancement of MTHFD2 expression is correlated with poor prognosis of breast cancer. It was also reported that if expression of MTHFD2 in cancer cells is inhibited by RNA interference, growth of the cancer cells decreases and cell death occurs significantly. MTHFD2 expression is observed in a developing embryo and is scarcely found in tissues of healthy adults even though the tissues are growing. Because of this, agents inhibiting MTHFD2 are expected to be useful as anti-cancer agents with fewer adverse drug reactions.
As compounds inhibiting MTHFD2, several folic acid analogues are known so far (Non Patent Literatures 2, 3).